Clinics in Dermatology (2005) 23,47–55

Genetic and nail disorders

Eli Sprecher, MD, PhD*

Department of Dermatology and the Laboratory of Molecular Dermatology, Rambam Medical Center, Haifa 31096, Israel

Abstract Hair and nails are skin appendages that share with other ectodermal tissues a common developmental pathway. Inherited disorders affecting these two structures therefore very often involve other epithelial components and present with multiple anomalies, generating both physical and psychological distress among patients and their families. The present review briefly describes major recent advances in our understanding of hair and nail genodermatoses. D 2005 Elsevier Inc. All rights reserved.

Absence of hair or nails is obviously compatible with tioned in this review are exceedingly rare, genetic testing is normal lifespan, yet patients often experience the loss of often exclusively offered by the research laboratories either one of these two skin appendages as a very investigating those diseases. detrimental condition, affecting many aspects of their personal and social life. In addition, today little relief can be offered to affected individuals. During the last decade, development through the study of rare genetic disorders, much has been learned about the physiology of hair and nail development, Hair follicles start to develop during the 10th week of generating much hope for better and more rationale gestation, when a mesoderm-derived signal induces overly- treatment approaches in the future. A complete discussion ing ectodermal cells to form the primordial hair follicle bud. of all hereditary nail and hair disorders is beyond the scope Subsequently, specialized mesenchymal cells form the of this article. The following review succinctly describes dermal papilla located at the bottom of the growing hair recent and major avenues of research in hair and nail follicles and responsible for generating mesenchymal growth 1 inherited disorders, based on a number of selected exam- and differentiation factors. Competition between various ples. Tables 1-3 present a more exhaustive list of disorders morphogenetic stimulatory (eg, sonic hedgehog) and inhib- for which mutations in specific genes or linkage to specific itory proteins (eg, bone morphogenetic proteins) eventually chromosomal loci have been described. Relevant references determines the final distribution and density of hair fol- 2,3 can be searched for at http://www.ncbi.nlm.nih.gov/entrez/ licles. At birth, about 5 million of hair follicles cover the query.fcgi?db=OMIM. General guidelines for genetic testing body surface and no additional follicles are formed for the various diseases in this article can be found at http:// thereafter. The mature hair follicle, however, continues to www.genetests.org/. Because many of the disorders men- grow in a cyclical fashion, progressing through 3 distinct phases known as anagen (growth phase), catagen (regres- * Tel.: +972 4 8541919; fax: +972 4 8542951. sion phase), and telogen (resting phase). Hair cycling E-mail address: eÀ[email protected]. recapitulates follicular morphogenesis in many aspects

0738-081X/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2004.09.009 48 E. Sprecher

Table 1 Genodermatoses with prominent hair anomalies Disorder Inheritance MIM Locus Gene Isolated hair disorders AUC AR 203655 8p21 HR APL AR 209500 8p21 HR Congenital generalized hyportrichosis XLR 307150 Xq24-q27.1 Unknown Hyportrichosis simplex AD 146520 6p21 CDSN AD 605389 18p11.32 Unknown Localized autosomal recessive hypotrichosis AR 607903 18q12 DSG4 AD 600628 12q13 K6hf Marie Unna hypotrichosis AD 146550 8p21 Unknown

Syndromic hair disorders Androgen insensitivity syndrome XLR 313700 Xq11-q12 AR Argininosuccinicaciduria AR 207900 7cen-q11.2 ASL Bamforth-Lazarus syndrome AR 241850 9q22 FKHL15 Bazex syndrome XLD 301845 Xq24-q27 Unknown Berardinelli-Seip syndrome AR 269700 9q34 AGPAT2 11q13 BSCL2 Biotinidase deficiency AR 253260 3p25 BTD Bjfrnstad syndrome AR 262000 2q34-q36 Unknown Chondrodysplasia punctata XLD 302960 Xp11.23 EBP Cornelia de Lange syndrome AD 122470 3q26.3 NIPBL Carvajal syndrome AR 605676 6p24 DSP AR 256850 16q24.1 GAN Griscelli syndrome AR 607624 15q21 MYO5A, RAB27A Hypohidrotic XLR 305100 Xq12-q13 EDA AD 224900 2q11-q13 EDAR Hypotrichosis with juvenile macular dystrophy AR 601553 16q22.1 CDH3 Hypotrichosis--telangiectasia syndrome AR 607823 20q13.33 SOX18 , leukocyte vacuoles, alopecia, and sclerosing cholangitis AR 607626 3q27-q28 CLDN1 follicularis spinulosa decalvans cum XLR 308800 Xp22.2-22.13 Unknown Keratitis-ichthyosis-deafness syndrome AD 148210 13q11-q12 GJB2, GJB6 Leprechaunism AR 246200 19p13.2 INSR XLR 309400 X12q-q13 ATP7A Naxos disease AR 601214 17q21 JUP NTS AR 256500 5q32 SPINK5 Oculocutaneous albinism, type I AR 203100 11q14-q21 TYR Oculocutaneous albinism, type II AR 203200 15q11.2 P Oculodentodigital dysplasia AD 164200 6q21-q23.2 GJA1 Orofaciodigital syndrome XLD 311200 Xp22.3 CXORF5 Progeria syndrome AD 176670 1q21.2 LMNA Vitamin D–resistant rickets AR 277440 12q12-q14 VDR Waardenburg syndrome I AD 193500 2q35 PAX3 Waardenburg syndrome IIA AD 193510 3p14.1 MITF Werner syndrome AR 277700 8p12-p11.2 RECQL2 because it involves the proliferation and differentiation of Disorders of hair morphogenesis epithelial stem cells in response to dermal papilla-derived signals.4,5 A number of additional anatomical, hormonal, In this group of disorders, abnormal hair is evident at nutritional, and genetic factors further modulate hair shaft birth and persists throughout life. size, shape, and color.1 This developmental scheme forms the basis for the classification of inherited hair disorders Hypotrichosis with juvenile macular dystrophy into disorders of hair morphogenesis, hair cycling, and hair shaft structure. The dual role played by a number of This rare autosomal recessive disorder is characterized by molecules during hair morphogenesis and hair cycling short and sparse hair at birth, which predicts the later accounts for the great deal of overlap existing between the occurrence of progressive macular degeneration (Fig. 1), different groups of hair genodermatoses. eventually leading to blindness during the first to fourth Genetic hair and nail disorders 49

Table 2 Genodermatoses with prominent nail anomalies Disorder Inheritance MIM Locus Gene Isolated nail disorders Isolated congenital nail dysplasia AD 605779 17p13 Unknown

Syndromic nail disorders Brachydactyly, type B1 AD 113000 9q22 ROR2 Darier disease AD 124200 12q23-q24.1 ATP2A2 Huriez syndrome AD 181600 4q23 Unknown Nail patella syndrome AD 256020 9q34.1 LMX1B Otopalatodigital syndrome, type I XLD 311300 Xq28 FLNA Pallister-Hall syndrome AD 146510 7p13 GLI3 Pycnodysostosis AR 265800 1q21 CTSK Rubinstein-Taybi syndrome AD 180849 16p13.3 CREBBP Scleroosteosis AR 269500 17q12-q21 SOST Witkop syndrome AD 189500 4p16.1 MSX1 AD 153300 16q24.3 FOXC2 decade of life.6 Histologically, a high ratio of vellus to pseudomonilethrix.7 Normal hair shaft structure, however, terminal hair as well as a high number of regressing hair has also been observed.6 The disease maps to 16q21, which follicles have been reported. Hair microscopy reveals a harbors a cluster of classical cadherins, the major compo- number of morphological anomalies such as and nents of adherens junctions. Deleterious mutations have

Table 3 Genodermatoses with combined hair and nail anomalies Disorder Inheritance MIM Locus Gene Cartilage hair hypoplasia AR 250250 9p21-p12 RMRP CHILD syndrome XLD 308050 Xq28 NSDHL Coffin-Lowry syndrome XLD 306600 Xp22.2p.22.1 RPS6KA3 AD 218040 22q13.1 Unknown XLR 305000 Xq28 DKC1 AD 127550 3q21-q28 TERC Ectodermal dysplasia – hidrotic type AD 129500 13q11-q12 GJB6 Ectodermal dysplasia – Margarita Island type AR 225060 11q23-24 PVRL1 Ectodermal dysplasia/skin fragility AR 604536 1q32 PKP1 Ellis-van Creveld syndrome AR 225500 4p16 EVC, EVC2 AR, AD 131760, 226700, 12q13, 17q12, K5, K14, LAMA3, (simplex, junctional, and dystrophic) 226650, 131750 6q22, 1q25, 3p31.3, LAMB3, LAMC2, 18q11.2, 10q24.3 COL17A1, COL7A1 Hay-Wells syndrome; Ectrodactyly, AD; AD 106260; 129900 3q27 p63 ectodermal dysplasia, and cleft lip/palate syndrome Hereditary bullous dystrophy, macular type XLR 302000 Xq27.3-ter Unknown XLD 308300 Xq28 NEMO Lymphedema-distichiasis syndrome AD 153400 16q24.3 FOXC2 AD 158000 12q13 hHb1, hHb6 Naegeli-Franceschetti-Jadassohn syndrome AD 161000 17q11.2-q21 Unknown PC-1/PC-2 AD 167200 12q13 K6a,K6b, K16, K17 167210 17q12-q21 Rothmund-Thomson syndrome AR 268400 8q24.3 REQL4 Sotos syndrome Sporadic 117550 5q35 NSD1 T-cell immunodeficiency, AR 601705 17q11-q12 WHN congenital alopecia, and nail dystrophy Trichodentoosseous syndrome AD 190320 17q21.3-q22 DLX3 Trichorhinophalangeal syndromes AD 190350 8q22-8q24 TRPS1 (EXT1) 150230 190351 AR 601675 19q13.2-q13.3 TFIIH/XPD 50 E. Sprecher

Fig. 1 a, Hypotrichosis of scalp. b, Severe macular pigmentary degenerative changes in a patient with hypotrichosis with juvenile macular dystrophy. been identified in families of various ethnic origins in tions underscore the importance of cell-cell junctions during CDH3, which encodes P-cadherin, a transmembranal hair morphogenesis. classical cadherin expressed in hair follicles and retinal pigment epithelium.7-9 The exact pathomechanism underly- ing the clinical manifestations of hypotrichosis with juvenile macular dystrophy (MIM601553) is still elusive. Interest- Disorders of hair cycling ingly, b-, which is bound to the intracytoplasmic part In this group of disorders, hair is normally distributed at of P-cadherin, has been shown to play a major role during birth and becomes sparse or absent later. hair morphogenesis through down-regulation of E-cadherin expression.3 As a result, under physiological conditions, P- Atrichia with papular lesions cadherin remains the major classical cadherin being expressed at sites of mesenchymal-epithelial contacts during Affected children are usually born with normal hair, the early stages of hair differentiation. This may explain the which is shed during the first months of life. During the first consequences of P-cadherin deficiency on hair morphogen- to second decade of life, patients develop a diffuse papular esis in hypotrichosis with juvenile macular dystrophy. rash, which has been noted to be particularly prominent over the cheeks and scalp but can involve almost any part of the 16 Localized autosomal recessive hypotrichosis body. Various associations with mental retardation, gastrointestinal polyposis, and delay in bone age have Localized autosomal recessive hypotrichosis (MIM rarely been reported.17-19 Another inherited form of 607903) was recently described in 2 Pakistani families. congenital atrichia, termed congenita Affected individuals display sparse hair over the scalp, (AUC; MIM203655), is clinically identical to atrichia with chest, arms, and legs.10 In addition, small papules are visible papular lesions (APL; MIM209500) except for the absence over some parts of the scalp. Examination of skin biopsies of skin papules.20 Alopecia universalis congenita was reveals atrophic and coiled hair shafts as well as a marked initially mapped to 8p21.2, which harbors the hairless swelling of the precortical region, reflecting a defect in (HR) gene.21,22 Mutation analysis of APL/AUC families of differentiation with concomitant epithelial hyperprolifera- various ethnic origins revealed the existence of a large tion. The disease was mapped to 18q12 and shown to result number of pathogenic mutations scattered over the entire from deleterious mutations in a novel gene encoding length of the HR gene (reviewed in ref. 23). Most of these desmoglein 4,10 a major desmosomal cadherin in the hair mutations result in premature termination of protein follicle.11 Interestingly, a number of additional desmosomal translation. Full delineation of the consequences of missense proteins have been shown to be involved in the pathogenesis mutations in the HR gene awaits a better understanding of of inherited hair disorders including corneodesmosin, the function of the hairless protein. Hairless is highly 1, and and , which expressed in the skin and the brain.24 It is thought to are abnormally expressed in hypotrichosis simplex function as a transcription factor and contains a zinc-finger (MIM146520), skin fragility/ectodermal dysplasia domain, which was found to be affected by a mutation (MIM604536), and woolly hair with palmoplantar kerato- segregating with AUC in several families.25,26 The hairless derma and cardiomyopathy syndrome (MIM610214/ protein is located within the nucleus in association with the MIM605676), respectively.12-15 Altogether, these observa- nuclear matrix.27 Nuclear matrix-associated hairless may Genetic hair and nail disorders 51 regulate the activity of other transcription factors such as the domains responsible for DNA binding and interactions with thyroid hormone receptor, with which hairless has been other proteins. Mutations at this site generally cause VDRR shown to physically and functionally interact.28 Interesting- type IIa. In contrast, several mutations in the vitamin D– ly, a homozygous HR missense mutation, causing AUC, binding domain, situated at the C-terminus, were shown not was found to affect an amino acid residue previously shown to cause alopecia. Thus, vitamin D binding to the VDR is to play a role in rat hairless binding to the thyroid hormone not necessary for normal hair development, which may receptor.23 Absence of functional hairless protein results in explain why other forms of inherited rickets, with defective disintegration of hair follicles and their transformation into vitamin D binding, are not associated with alopecia.33 rudimentary . This phenomenon may be caused by the These studies emphasized the importance of VDR binding loss of contact between the dermal papilla and the overlying to DNA and its interactions with other transcription factors follicular epithelium shortly after the entry of the hair during hair cycling. Because VDRR bears significant follicle into the first catagen phase.29 Thus, hairless seems to clinical and histological similarities to APL (Fig. 2), it has regulate the transition from anagen to catagen during hair been suggested that VDR and hairless may be involved in cycling. Given that the common androgenetic alopecia is the same pathophysiological pathway.35 Interestingly, muta- thought to result from abnormal kinetics of hair cycling, tions in the murine HR and VDR genes have been shown to hairless was anticipated to play a role in androgenetic result in phenotypes resembling their human counterparts, alopecia pathogenesis. Two studies failed, however, to APL and VDRR.35 In addition, retinoid X receptor-a provide convincing evidence in support of a major etiologic ablation and overexpression of the ornithine decarboxylase role of hairless in androgenetic alopecia.30,31 gene have been shown in mice to lead to both alopecia and dermal formation.36,37 The exact nature of the Vitamin D–resistant rickets functional interactions between hairless, members of the steroid family of nuclear receptors, and ornithine decarbox- Vitamin D–resistant rickets (VDRR; MIM277440) is ylase is still unclear. inherited in an autosomal recessive fashion. It was shown to result from end organ unresponsiveness to 1,25-dihydroxy- cholecalciferol. Affected patients display normal serum 25- Disorders of the hair shaft structure hydroxyvitamin D, high serum 1,25-(OH)2-cholecalciferol and profound hypocalcemia, which manifests with seizures In hair shaft structural disorders, hair follicles develop and and tetany.32 Affected individuals present early in child- are able to cycle but display a defective structure, which often hood with chronic rickets, resulting in progressive bone results in aberrant hair distribution, color, length, or texture. abnormalities and loss of teeth. Vitamin D–resistant rickets Monilethrix with (type IIa) must be differentiated from VDRR without hair loss (type IIb). Patients with VDRR type IIa This autosomal dominant disorder is characterized by are born with normal hair, which is shed during the first the appearance of beaded hair shafts due to the presence of year of life and never significantly regrows thereafter. In alternating segments of normal and abnormally low contrast, bony changes can improve with age.33 Milia-like diameters. tend to break at the constricted sites, lesions similar to those observed in APL have also been resulting in varying degrees of alopecia with short and described in VDRR. The disorder was first shown in 1988 sparse hair over the scalp. Abnormal hairs may be visible at to result from mutations in the gene encoding the vitamin birth or, more often, during the first months of life. Marked D3 receptor (VDR), which is located on 12q12-q14.34 Most interfamilial and intrafamilial variations in disease severity of the disease-causing mutations are located within the N- have been observed. In addition, patients may display terminal DNA-binding domain, which harbors 2 zinc-finger prominent follicular as well as various nail

Fig. 2 Total atrichia in 2 patients with (a) APL and (b) VDRR. 52 E. Sprecher abnormalities.38 The disease was mapped to 12q11-q13 in epithelial differentiation. Cell-cell junction reorganization 1996.39 A year later, studying a large affected British may be pivotal during both epidermal barrier ontogenesis50 family, Winter et al40 identified a pathogenic mutation in and hair shaft formation.7,10 Because LEKTI may function the hair cortex-specific gene, hHb6. Since then, a by inhibiting these epidermal proteases, decreased LEKTI number of substitutions have been identified in the central activity may logically lead to excessive proteolytic activity a-helical rod coding region of the hHb6 and hHb1 hair within the follicle and epidermis, possibly explaining keratin genes.41 Monilethrix (MIM158000) hairs have also abnormal hair shaft and barrier development in NTS. been observed in Menkes’ syndrome, an X-linked disorder Supporting that possibility are recent observations demon- characterized by neurological and hair manifestations due strating increased hydrolytic activity in the to deleterious mutations in the ATPA7A gene, encoding a of patients with NTS.51 copper-binding protein.42 Abnormal posttranslational pro- cessing of keratin molecules due to intracellular copper deficiency may explain the common occurrence of beaded Nail development hair in monilethrix and Menkes’ syndrome. Nail development starts around the ninth week of Netherton syndrome gestation and is completed during the fifth month of pregnancy. Little is currently known about the molecular The autosomal recessive Netherton syndrome (NTS, signals regulating nail morphogenesis. A number of MIM256500) is characterized by a triad of symptoms, homeobox and transcription factors such as the Msx which include congenital ichthyosis, atopic features, and proteins and LMX1B, a LIM-homeodomain transcription hair structural abnormalities. The syndrome often manifests factor, have been implicated in the control of this process, soon after birth with generalized erythroderma and scaling. although the details of the way they affect nail development Due to breakdown of the epidermal barrier, newborns are at remain poorly explored.52,53 The mature nail plate grows risk for numerous and often life-threatening complications continuously through life as a result of matrix epithelial cell such as hypernatremic dehydration and other electrolyte differentiation and consists of a number of hard and soft imbalances, impaired thermoregulation, and systemic infec- keratin molecules embedded in an amorphous matrix. Most tions. Some patients remain erythrodermic for their entire inherited nail disorders manifest either with nail hypoplasia lifetime, whereas, in others, the ichthyosis evolves into or nail hypertrophy. ichthyosis linearis circumflexa, characterized by migratory, serpiginous plaques bordered by a peculiar double-edged scale (reviewed in Ref. 43). These cutaneous features are Nail hypoplasia invariably accompanied by atopic manifestations such as allergic rhinitis, asthma, allergic reactions to food and Isolated congenital nail dysplasia common antigens, and elevated IgE levels. Increased susceptibility to skin, respiratory tract or systemic infec- Isolated nail dysplasia is rare and most probably tions, malnutrition, and failure to thrive are also character- represents a very heterogeneous group of disorders. Some istic. Hair abnormalities, in contrast with skin changes, are patients with isolated congenital nail dysplasia have been seldom apparent before the first year of age. At that time, shown to carry mutations in genes known to be associated hair microscopy can reveal the characteristic bamboo hairs with complex genodermatoses such as COL7A1, associated or , which underlie a progressive with dystrophic epidermolysis bullosa, and GJB6, defective alopecia involving the eyebrows first and scalp areas later in hidrotic ectodermal dysplasia, implying that these cases 44 do not represent more than formes frustes of those on. This hair abnormality is thought to result from 54,55 abnormal keratinization leading to intussusception of the disorders. True isolated congenital nail dysplasia was fully keratinized distal hair shaft into the proximal partially shown to segregate in an autosomal dominant fashion in a keratinized hair shaft. Other abnormalities including pili large multigenerational German family in which affected members display thinning and impaired formation of torti (twisted hair) and (hair of varying 56 diameter) have also been observed in children with NTS. fingernail and toenail plates. Recently, Krebsova et al The disorder was shown to result from pathogenic mutations successfully mapped isolated congenital nail dysplasia in in SPINK5, located on 5q32,45-47 resulting in decreased this family to a 6-cM interval on 17p13. expression of a large inhibitor termed Nail patella syndrome LEKTI.48 How hair abnormalities are related to decreased levels of a serine protease inhibitor is still a matter of debate. Nail patella syndrome (NPS; MIM256020) is dominantly Of interest is a number of publications describing the inherited and is characterized by a number of nail anomalies expression of functional proteases within the hair follicle ranging from slight longitudinal ridging, nail splitting, and and epidermis.49 These proteases have been hypothesized to nail fragility to generalized nail hypoplasia or aplasia play a role in the dissolution of cell-cell junctions during (). A triangular or V-shaped lunula is particularly Genetic hair and nail disorders 53 typical. The second major feature in this disorder involves defects in by A Irvine). the patella, which can be either absent or hypoplastic. Other type 1 (PC-1; MIM167200; Jadassohn-Levandowsky syn- bony deformations such as iliac horns, elongated radius with drome) is characterized by nail thickening and yellowish hypoplasia of radial head, elbow deformities, and rib discoloration due to subungual hyperkeratosis, focal hypoplasia have been described. Ocular signs including palmoplantar , follicular hyperkeratosis, and corneal malformations, congenital cataract, iris pigmenta- oral leukokeratosis. Pachyonychia congenita type 2 (PC-2; tion (Lester’s sign) are variable manifestations of the MIM167210; Jackson-Lawler syndrome) is accompanied syndrome. Finally, a large proportion of patients with NPS by less severe nail dystrophy and milder keratoderma and develop progressive glomerulopathy manifesting with mas- is readily distinguished by the presence of multiple sive proteinuria and sometimes resulting in end-stage renal steatocystomas and a history of neonatal teeth (Fig. 3). failure.57 Mutations in LIM homeobox transcription factor 1 Both disorders are inherited in an autosomal dominant (LMX1B) gene, located on 9q34.1, were found to underlie fashion. Additional variants with corneal leukokeratosis NPS in most affected kindreds.58 The protein encoded by (PC type 3) and laryngeal lesions with mental retardation this gene is a transcription factor. It was shown to play a (PC type 4) have also been described. Pachyonychia central role in limb development, which may explain why congenita type 1 results from mutations in K6a or K16 LMX1B dysfunction leads to bone and nail abnormal mor- keratin genes whereas PC-2 is caused by mutations in K6b phogenesis. Interestingly, mutant LMX1B is thought to lead and K17 keratin genes (reviewed in Ref. 60). The pattern to the NPS phenotype due to aberrant patterning along the of expression of these 2 pairs of keratin explain the proximal-distal and anterior-posterior axes. In this regard, it specific clinical manifestations of the 2 PC subtypes: is of note that a gradual increase in severity of nail keratins 6a and 16 are expressed in the nail bed and nail dystrophy has been observed in NPS from thumbs to little fold as well as in palmoplantar skin and oral mucosae; fingers.57 Finally, LMX1B was shown to regulate the keratins 6b and 17 are found in the nail bed, hair follicle, expression of collagen IV, a major component of the and eccrine glands as well as in selected areas of glomerular basement membrane, which may explicate the palmoplantar skin. Marked phenotypic variability has been renal pathology in NPS.59 observed in this group of disorders. For example, mutations in K16 have been shown to underlie kerato- derma in the absence of nail changes typical of PC-1,61 Nail hypertrophy and mutations in K17 have been shown to cause Pachyonychia congenita type 1 and type 2 with no other manifestation of PC-2.62 To complicate the picture even further, combined Hallmarks of pachyonychia congenita (PC) are greatly features of PC-1 and PC-2 have recently been shown to thickened and malformed nail plates (see also Inherited result from a deleterious mutation in K6a.63

Fig. 3 a, Nail thickening and yellowish discoloration. b, Steatocystoma multiplex (arrows). C, Focal in a patient with PC-2. 54 E. Sprecher

Conclusions 13. McGrath JA, McMillan JR, Shemanko CS, et al. Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility The molecular basis of a steadily growing number of syndrome. Nat Genet 1997;17:240-4. genetic hair and nail disorders has been elucidated during 14. McKoy G, Protonotarios N, Crosby A, et al. Identification of a deletion the last decade. This rapidly expanding body of information in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). has already brought major changes in the life of families Lancet 2000;355:2119-24. afflicted by these disorders by providing them with a 15. Norgett EE, Hatsell SJ, Carvajal-Huerta L. Recessive mutation in definitive diagnosis and, when indicated, with the possi- desmoplakin disrupts desmoplakin- interactions bility of premarital counseling and prenatal diagnosis. Our and causes , woolly hair and keratoderma. Hum ultimate goal remains the application of this novel Mol Genet 2000;9:2761-6. 16. Sprecher E, Bergman R, Szargel R. Atrichia with papular lesions maps knowledge to foster the development of innovative to 8p in the region containing the human hairless gene. Am J Med therapies to alleviate and possibly cure our patients’ Genet 1998;80:546-50. disease. The burgeoning science of topical gene therapy, 17. Ishii Y, Kusuhara T, Nagata T. Atrichia with papular lesions associated which is of particular relevance to the treatment of skin with gastrointestinal polyposis. J Dermatol 1979;6:111-6. appendage disorders, has already generated fascinating 18. del Castillo V, Ruiz-Maldonado R, Carnevale A. Atrichia with papular 64 lesions and mental retardation in two sisters. Int J Dermatol 1974;13: observ atio ns , which sugges t that this goal may not be 261-5. out of reach. 19. Kruse R, Cichon S, Anker M. Novel hairless mutations in two kindreds with autosomal recessive papular atrichia. 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Cichon S, Anker M, Vogt IR, et al. Cloning, genomic organization, loss and its treatment. Trends Mol Med 2001;7:293-301. alternative transcripts and mutational analysis of the gene responsible 3. Jamora C, DasGupta R, Kocieniewski P, et al. Links between signal for autosomal recessive universal congenital alopecia. Hum Mol Genet transduction, transcription and adhesion in epithelial bud development. 1998;7:1671-9. Nature 2003;422:317-22. 25. Aita VM, Ahmad W, Panteleyev AA, et al. A novel missense mutation 4. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the (C622G) in the zinc-finger domain of the human hairless gene bulge area of pilosebaceous unit: implications for follicular stem cells, associated with congenital atrichia with papular lesions. Exp Dermatol hair cycle, and skin carcinogenesis. Cell 1990;61:1329-37. 2000;9:157-62. 5. Panteleyev AA, Jahoda CA, Christiano AM. Hair follicle predetermi- 26. Ahmad W, Nomura K, McGrath JA, et al. A homozygous nonsense nation. J Cell Sci 2001;114:3419-31. mutation in the zinc-finger domain of the human hairless gene 6. Raison-Peyron N, Duval PA, Barneon G, et al. A syndrome combining underlies congenital atrichia. J Invest Dermatol 1999;113:281-3. severe hypotrichosis and macular dystrophy: absence of mutations in 27. Djabali K, Aita VM, Christiano AM. Hairless is translocated to the TIMP genes. Br J Dermatol 2000;143:902-4. nucleus via a novel bipartite nuclear localization signal and is 7. Sprecher E, Bergman R, Richard G, et al. Hypotrichosis with juvenile associated with the nuclear matrix. J Cell Sci 2001;114:367-76. macular dystrophy is caused by a mutation in CDH3 encoding P- 28. Potter GB, Beaudoin III GM, DeRenzo CL, et al. The hairless gene cadherin. Nat Genet 2001;29:134-6. mutated in congenital hair loss disorders encodes a novel nuclear 8. Indelman M, Bergman R, Lurie R, et al. A missense mutation in CDH3, receptor corepressor. 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